uPAR Controls Vasculogenic Mimicry Ability Expressed by Drug-Resistant Melanoma Cells

Malignant melanoma is a highly aggressive skin cancer characterized by an elevated grade of tumor cell plasticity. Such plasticity allows adaptation of melanoma cells to different hostile conditions and guarantees tumor survival and disease progression, including aggressive features such as drug resistance. Indeed, almost 50% of melanoma rapidly develop resistance to the BRAFV600E inhibitor vemurafenib, with fast tumor dissemination, a devastating consequence for patients’ outcomes. Vasculogenic mimicry (VM), the ability of cancer cells to organize themselves in perfused vascular-like channels, might sustain tumor spread by providing vemurafenibresistant cancer cells with supplementary ways to enter into circulation and disseminate. Thus, this research aims to determine if vemurafenib resistance goes with the acquisition of VM ability by aggressive melanoma cells, and identify a driving molecule for both vemurafenib resistance and VM. We used two independent experimental models of drug-resistant melanoma cells, the first one represented by a chronic adaptation of melanoma cells to extracellular acidosis, known to drive a particularly aggressive and vemurafenib-resistant phenotype, the second one generated with chronic vemurafenib exposure. By performing in vitro tube formation assay and evaluating the expression levels of the VM markers EphA2 and VE-cadherin by Western blotting and flow cytometer analyses, we demonstrated that vemurafenib-resistant cells obtained by both models are characterized by an increased ability to perform VM. Moreover, by exploiting the CRISPR-Cas9 technique and using the urokinase plasminogen activator receptor (uPAR) inhibitor M25, we identified uPAR as a driver of VM expressed by vemurafenib-resistant melanoma cells. Thus, uPAR targeting may be successfully leveraged as a new complementary therapy to inhibit VM in drug-resistant melanoma patients, to counteract the rapid progression and dissemination of the disease.     

Placental metal concentrations and birth outcomes: The Environment and Childhood (INMA) project

Objective

To examine the association of placental levels of arsenic (As), cadmium (Cd), mercury (Hg), lead (Pb), manganese (Mn), and chromium (Cr) with birth outcomes (birth weight, length, and head circumference, low birth weight [LBW], gestational age, preterm delivery, and small for gestational age [SGA]) in mother-child pairs from the Environment and Childhood (INMA) Project in Spain.

Free Bipedicled Radial Forearm and Posterior Interosseous Artery Perforator Flap Phalloplasty

IntroductionThe free radial forearm (FRFA) flap is universally still considered as the gold standard technique in penile reconstruction. Typically, a considerably large flap is required, often involving almost the entire circumference of the forearm. Partial necrosis may occur at the distal-most (dorsoradial) part of the flap as a result of insufficient perfusion.AimTo describe a new technique using the posterior interosseous artery (PIOA) to supercharge FRFA phalloplasty.MethodsIn a 12-month period, all patients having FRFA flap phalloplasty were enrolled. Perioperative, after complete flap dissection, an indocyanine green perfusion scan was performed. In case of insufficient perfusion at the distalmost part of the flap, a supramicrosurgical anastomosis was performed between the FRFA pedicle and the PIOA (artery only).Main Outcome MeasuresStudied outcomes included the rate of marginal necrosis, surgical time, postoperative posterior interosseous nerve damage and urethral complications (fistula, stenosis or necrosis).ResultsA total of 27 FRFA flap phalloplasties was performed. Anastomosis of the PIOA was needed in 15 cases. No marginal necrosis was observed in these cases. There were no cases of postoperative posterior interosseous nerve damage. There were no significant differences in urethral complications (fistula, stenosis or necrosis) between the 2 groups.Clinical ImplicationsIn selected cases where insufficient perfusion of the dorsoradial part of the flap is present, patients may benefit from arterial supercharging to prevent postoperative marginal necrosis.Strength & LimitationsStrengths include a single surgeon, thus lending continuity of skill and technique, a consecutive series, and 100% short-term follow-up. Limitations include single institution series and a limited number of patients.ConclusionArterial supercharging is effective in improving perfusion of large FRFA flaps used in phalloplasty when dorsoradial hypoperfusion is detected on an indocyanine green perfusion scan. It is a technically challenging addition to the standard technique because of the small size of the vessels, the close relationship between the PIOA and the posterior interosseous nerve, and the vulnerability of the newly constructed intra-flap anastomosis.De Wolf E, Claes K, Sommeling CE, et al. Free Bipedicled Radial Forearm and Posterior Interosseous Artery Perforator Flap Phalloplasty. J Sex Med 2019;16:1111–1117.     

Individuals with peripheral vestibulopathy and poor quality of sleep are at a higher risk for falls

IntroductionThere is a lack of scientific studies on the assessment of patients with vestibular disorders associated with sleep quality disorders and its impact on the balance and overall quality of life.Objectivesto assess the impact of the sleep quality on the balance and quality of life of individuals with peripheral vestibulopathies.Methods52 individuals with peripheral vestibulopathies underwent sleep quality assessment through the Pittsburgh sleep quality index, neurotological examination through dizziness handicap inventory and Tetrax posturography (Sunlight Medical Ltd.) in eight sensory conditions. Thirty-two healthy individuals (G3) participated as the control group.ResultsFourteen individuals with vestibulopathy had good quality of sleep (G1) and 38 showed poor quality of sleep (G2) as demonstrated by the Pittsburgh sleep quality index global scores (p = 0.001). The dizziness handicap inventory showed worse impact of the dizziness on the quality of life in G2 when compared to G1 (p  = 0.045). The G₂ showed higher risk of falling in posturography when compared to G3 (p = 0.012) and higher index of postural instability in five sensory conditions in comparison with G3. In the vestibulopathy groups, the worse the sleep quality, the higher the risk of falling (r = 0.352) and the worse the quality of life (r = 0.327).ConclusionIndividuals with peripheral vestibulopathies and poor quality of sleep demonstrate worse balance evidenced by increased postural instability, higher risk of falls and worse perceived quality of life. The quality of sleep is a predictive factor for worse perceived quality of life and for higher risk of falls in individuals with peripheral vestibulopathies.     

COVID-19 in the endoscopy unit: How likely is transmission of infection? Results from an international,multicenter study

BACKGROUND Coronavirus disease 2019(COVID-19) significantly affected endoscopy practice,as gastrointestinal endoscopy is considered a risky procedure for transmission of infection to patients and personnel of endoscopy units(PEU).AIM To assess the impact of COVID-19 on endoscopy during the first European lockdown(March-May 2020).METHODS Patients undergoing endoscopy in nine endoscopy units across six European countries during the period of the first European lockdown for COVID-19(MarchMay 2020) were included. Prior to the endoscopy procedure, participants were stratified as low-or high-risk for potential COVID-19 infection according to the European Society of Gastrointestinal Endoscopy(ESGE) and the European Society of Gastroenterology and Endoscopy Nurses and Associates(ESGENA) joint statement, and contacted 7-14 d later to assess COVID-19 infection status. PEU were questioned regarding COVID-19 symptoms and/or infection via questionnaire, while information regarding hospitalizations, intensive care unitadmissions and COVID-19-related deaths were collected. The number of weekly endoscopies at each center during the lockdown period was also recorded.RESULTS A total of 1267 endoscopies were performed in 1222 individuals across nine European endoscopy departments in six countries. Eighty-seven(7%) were excluded because of initial positive testing. Of the 1135 pre-endoscopy low risk or polymerase chain reaction negative for COVID-19, 254(22.4%) were tested post endoscopy and 8 were eventually found positive, resulting in an infection rate of 0.7% [(95%CI: 0.2-0.12]. The majority(6 of the 8 patients, 75%) had undergone esophagogastroduodenoscopy. Of the 163 PEU, 5 [3%;(95%CI: 0.4-5.7)] tested positive during the study period. A decrease of 68.7%(95%CI: 64.8-72.7) in the number of weekly endoscopies was recorded in all centers after March 2020. All centers implemented appropriate personal protective measures(PPM) from the initial phases of the lockdown.CONCLUSION COVID-19 transmission in endoscopy units is highly unlikely in a lockdown setting, provided endoscopies are restricted to emergency cases and PPM are implemented.